title: How delayed graft function impacts exposure to mycophenolic acid in patients after renal transplantation.
abstract: BACKGROUND
  Mycophenolic acid (MPA) plasma concentrations are highly variable on standard-dose mycophenolate mofetil therapy. At creatinine clearances below 25 mL/min, MPA clearance increases as a result of a higher nonprotein-bound fraction. Patients with delayed graft function (DGF) after renal transplantation are exposed to low total MPA concentrations, when risk of rejection is highest. This study investigated the influence of DGF on MPA exposure and on clinical outcome.
  
  
  METHODS
  Adult renal transplantation patients treated with mycophenolate mofetil, corticosteroids, and either microemulsified cyclosporine (n = 459) or tacrolimus (n = 371) participated in a randomized controlled trial (the Fixed-Dose Concentration-Controlled [FDCC] Study). Abbreviated MPA areas under the curve (AUCs) were obtained on Day 3, Day 10, Week 4, and Month 3, to calculate MPA AUC₀₋₁₂. Free MPA AUC values were available for a subgroup of patients (n = 269).
  
  
  RESULTS
  The overall incidence of DGF was 187 of 830 (23%) and did not differ between cyclosporine-treated (24%) and tacrolimus- (21%) treated patients. The incidence of biopsy-proven acute rejection at 12 months was significantly higher in patients with DGF (13.8% versus 21.4%). Patients with DGF had significantly lower dose-corrected MPA AUC on Day 3 and Day 10. Free MPA fraction and dose-corrected free MPA AUC were significantly higher in patients with DGF, from Day 3 until Month 3. The total number of patients with at least one opportunistic infection was significantly higher in patients with DGF (33.2%) compared with patients without DGF (25.8%) (P = 0.048). Patients with DGF developing opportunistic infections did not have higher total MPA AUC nor higher free MPA AUC compared with those without opportunistic infections.
  
  
  CONCLUSIONS
  Patients with DGF have significantly lower dose-corrected MPA AUC in the first month after renal transplantation, presumably as a result of enhanced MPA clearance on account of the elevated MPA free fraction. Because patients with DGF have a higher rate of acute rejection and lower MPA exposure, higher dosing of mycophenolate mofetil in such patients may improve outcome. However, the already increased incidence of opportunistic infections in patients with DGF is a concern.
authors.affiliation: Department of Hospital Pharmacy and Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. t.vangelder@erasmusmc.nl
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
authors.forename: Helio Tedesco
authors.initials: HT
authors.lastname: Silva
authors.forename: Hans
authors.initials: H
authors.lastname: de Fijter
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.forename: Dirk
authors.initials: D
authors.lastname: Kuypers
authors.forename: Richard D
authors.initials: RD
authors.lastname: Mamelok
authors.forename: Victor W
authors.initials: VW
authors.lastname: Armstrong
authors.forename: Michael
authors.initials: M
authors.lastname: Oellerich
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D019540:Area Under Curve; D003404:Creatinine / Q000097:blood / Q000378:metabolism; D016572:Cyclosporine / Q000627:therapeutic use; D051799:Delayed Graft Function / Q000378:metabolism*; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000150:complications; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009894:Opportunistic Infections / Q000150:complications; D016559:Tacrolimus / Q000627:therapeutic use; D017211:Treatment Failure
chemical_list: D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine; D009173:Mycophenolic Acid; D016559:Tacrolimus